NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of leadless cardiac pacemaker implantation for bradyarrhythmias Bradyarrhythmias (abnormal heart rhythms) can cause a slow heartbeat, usually because of a problem with the electrical system of the heart. In this procedure, a leadless cardiac pacemaker is inserted into the heart using a thin tube (catheter) through a large blood vessel in the groin (at the top of the leg). It is attached directly to the heart wall where it stimulates the heart to beat more quickly. This avoids the need for a pacemaker box under the skin with leads passing into the heart. The aim is to help the heart beat at a normal rate and reduce symptoms such as dizziness, shortness of breath, tiredness and fainting. Contents Introduction Description of the procedure Efficacy summary Safety summary The evidence assessed Validity and generalisability of the studies Existing assessments of this procedure Related NICE guidance Additional information considered by IPAC References Literature search strategy Appendix Page 1 of 62

2 Introduction The National Institute for Health and Care Excellence (NICE) prepared this interventional procedure overview to help members of the interventional procedures advisory committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in January 2018 and updated in July Procedure name Leadless cardiac pacemaker implantation for bradyarrhythmias Specialist societies British Heart Rhythm Society (BHRS) British Cardiovascular Society Royal College of Physicians. Description of the procedure Indications and current treatment Bradyarrhythmias are abnormal heart rhythms that can result in a slow heart rate (bradycardia), usually defined as less than 60 beats per minute. There are a range of causes including diseases such as sick sinus syndrome or atrioventricular block. The most common causes are the natural ageing process, ischaemic heart disease, heart valve disorders and heart failure. If untreated, bradycardia may lead to fatigue, fainting, palpitations, dizziness, heart failure and an increased risk of death. Bradyarrhythmias are managed with pacemakers as described in NICE technology appraisal guidance. Dual-chamber pacing is recommended for symptomatic bradycardia caused by sick sinus syndrome, atrioventricular block, or a combination of sick sinus syndrome and/or atrioventricular block, and also for sick sinus syndrome in people without atrioventricular block. Single-chamber ventricular pacemakers may be used for atrioventricular block alone or with sick Page 2 of 62

3 sinus syndrome in people with continuous atrial fibrillation, or people who have specific factors such as frailty or comorbidities that influence the balance of risks and benefits in favour of single-chamber pacing. What the procedure involves The aim of implanting a leadless cardiac pacemaker is to detect cardiac bradyarrhythmias and deliver electric pulses to the heart to increase the heart rate. The leadless pacemaker has a built-in pulse generator, battery and electrodes. The procedure is done under local anaesthesia, with or without sedation, in a cardiac catheterisation laboratory. Under fluoroscopic guidance, the proximal end of the pacemaker is attached to a deflectable bespoke delivery catheter system and inserted percutaneously through the femoral vein using a dedicated introducer sheath. It is then advanced into the right atrium through the tricuspid valve, into the right ventricle and positioned near the apex or lower septum. Contrast may be injected into the right ventricle to visualise the desired location. Once positioned, the pacemaker is deployed and securely implanted into the endocardial wall using a fixation mechanism (a screw-in helix or nitinol tines). An electrode at the distal end of the pacemaker delivers electrical impulses that pace the heart. Electrical measurements are taken and, if satisfactory, the pacemaker is released from the catheter and the catheter is removed. If the position is suboptimal, the pacemaker can be detached from the endocardium and repositioned prior to final release of the delivery catheter. The pacemaker is programmed using an external programmer that transmits signals to it. The pacemaker can be retrieved using a catheter retrieval system, if device dislodgement is discovered at follow-up. The device can only detect and pace the right ventricle (single chamber) in contrast to some conventional pacemakers that can provide dual-chamber (right atrium and right ventricle) detection and pacing. It is therefore suitable for people who only need single-chamber ventricular pacing. Efficacy summary Implantation outcomes In a case series of 33 patients implanted with leadless cardiac pacemakers (LCP), the implant success rate was 97% (32/33). The mean procedure duration was 28±17 minutes and average time to discharge was 31±20 hours. Repositioning after initial deployment was needed because of inadequate electrical measurements in 29% (9/33) of patients. More than 1 device was Page 3 of 62

4 implanted during the procedure in 15% (5/33) of patients because of inadvertent placement of the device in the left ventricle (n=1), malfunction of the release knob (n=1), delivery catheter damage related to tortuosity of the venous vasculature (n=1), damage to the device helix during insertion (n=1) and difficulty with the wire deflection mechanism of the delivery catheter (n=1). 1 In a case series of 526 patients, the LCP was successfully implanted in 96% (504/526) of patients who needed permanent single-chamber ventricular pacing. The mean procedure duration was 28.6±17.8 minutes and average time to discharge was 1.1±1.7 days. Repositioning after initial deployment was needed in 30% (150/504) of patients. 2 In a case series of 725 patients, the leadless transcatheter pacing system (TPS) was successfully implanted in 99% (719/725) of patients. Unsuccessful implantations (3 patients with cardiac perforations, 1 patient with pericardial effusion, 1 patient with tortuous venous anatomy, and 1 patient in whom pacing threshold could not be achieved) were reported in less than 1% (6/725) of patients. The mean procedure duration was 23.0±15.3 minutes (range 11 to 74 minutes). 4 In a case series of 795 patients, the TPS was successfully implanted in 97% (792/795) of patients. 77% of implantations needed 2 or more attempts of deployment. 6 Pacing performance In the case series of 33 patients implanted with LCP, the measures of pacing performance (sensing, impedance and pacing threshold) either improved or were stably within accepted range at 3, 6, 12 and 36 months follow-up (mean pacing threshold [at a 0.4-ms pulse width] 0.46 V, 0.40±0.26 V, 0.43±0.30 V and 0.47V; mean R-wave amplitude 10.6 mv, 10.6±2.6 mv, 10.3±2.2 mv and 10.8 mv; and mean impedance 627 ohms, 625±205 ohms, 627±209 ohms and 614 ohms) 1. Rate response sensor was activated in 61% (19/31) of patients at 12-month follow-up, 42% at 24 and 39% at 36 months follow-up. 1 In the case series of 526 patients with LCP, the measures of pacing performance improved statistically significantly from pacemaker implantation to 12 months (mean pacing threshold (at a 0.4-ms pulse width) from 0.82±0.69 V to 0.58±0.31V, p<0.01; mean R-wave amplitude from 7.8±2.9 mv to 9.2±2.9 mv, p<0.01; mean impedance from 700±295 ohms to 456±111 ohms, p<0.01). The intention to treat primary efficacy point (acceptable pacing performance at 6 months) was achieved in 90% [270/300] of the primary cohort (95% confidence interval [CI] 86% to 93.2%, p=0.007). 2 Page 4 of 62

5 In the case series of 725 patients with TPS, acceptable pacing performance was achieved in 93% (292/297) of the patients with paired 6-month data (95% CI, 96.1% to 99.5%; p<0.001) compared with the efficacy performance goal of 80% (based on historical transvenous control data). 4 The measures of pacing performance improved statistically significantly from pacemaker implantation (n=725) to 24 months (n=58) (mean pacing threshold (at a 0.24-ms pulse width) from 0.63 V to 0.53±0.23 V; mean R-wave amplitude from11.2 mv to 15.5 mv; mean pacing impedance from 724 ohms to 596 ohms). 4 In a retrospective matched case control study comparing pacing thresholds at implant and subsequent follow-up (0 to 6 months) between 711 patients with TPS with threshold data at 0.24 ms and 538 patients with transvenous leads at 0.4 ms, pacing thresholds in patients with elevated thresholds at implant (high more than 1.0 V or very high thresholds more than 1.5 V) decreased statistically significantly in both groups (TPS group: more than 1.0 V (n=45) : pacing threshold 87% decrease [1.28 to 0.78], p<0.001; more than 1.5 (n=27) pacing threshold 85% decrease [2.22 to 1.38], p<0.001; transvenous group more than 1.0 V (n=26) pacing threshold 80% decrease [1.31 to 0.85], p<0.001; more than 1.5V (n=19) pacing threshold 100% decrease [2.23 to 0.84], p<0.001). 5 In the case series of 795 patients with TPS, the measures of electrical performance were low and stable. Average pacing thresholds at implant (n=701), 3 months (n=39) and 6 months (n=25) were 0.6±0.5 V, 0.5±0.3 V and 0.6±0.3 V respectively. Average impedance was 721±181 ohms, 634±143 ohms, and 572±115 ohms. 6 In a retrospective comparative case series of 127 patients, acceptable sensing (R wave >5.0 mv) and pacing thresholds (<2.0 V at 0.4 ms) were reported in 95% (57/60) of patients in the LCP group and 97% (65/67) of patients in the CTP group (p=0.66). 10 Safety summary Overall complication rate In the case series of 33 patients with LCP, the overall complication-free rate was 94% (31/33) at 90-day follow-up and 90% (30/33) at 36-month follow-up. 1 In the case series of 725 patients with TPS, the overall device or procedurerelated major complication-free rate was 96% at 12 months (95% confidence interval [CI] 94.2 to 97.2%; p<0.001) compared with the safety performance goal of 83% (based on historical transvenous control data). 4 Page 5 of 62

6 In a propensity-matched analysis of 440 patients comparing LCP (n=220) and conventional transvenous pacemakers (CTP), device-related complication rate at 800-day follow-up was 0.9% (2/220) in the LCP group and 4.7% (10/220) in the CTP group when excluding pacemaker advisory related revisions (p=0.02). When including the pacemaker advisory revisions, device-related complication rate increased to 6.3% (14/220) in the LCP group and 4.7% (10/220) in the CTP group (p=0.063). 11 Device- or procedure-related serious adverse events Forty device- or procedure-related serious adverse events were reported in 6.5% (34/526) of patients in the case series of 526 patients with LCP at a mean followup of 6.9 months 2. In the primary cohort, 22 device-related serious adverse events were reported in 7% (20/300) patients at 6-month follow-up and 93% (280/300) of patients were free from these events and it exceeded the prespecified performance goal of 86% (p<0.001) (based on historical transvenous control data). 2 Serious adverse device effects (SADEs) were reported in 5.9% (20/339) of patients in the primary cohort (including after the study was paused) of the postmarket observational study of 470 patients with LCP at a mean follow-up of 19.5 months. 94.6% of patients were free from these events and demonstrated non-inferiority to a prespecified goal of 86% (p<0.001). The most frequently occurring events were cardiac perforation (1.5%), device dislodgement (0.3%), and vascular complications (1.5%). In the total cohort, 53 SADEs were observed in 10.6% (50/470) of patients. After stratifying the results in relation to the study pause, there was a statistically significant difference in the final LCP location (septum compared with apex; p<0.0001) and the number of repositioning attempts (<2 compared with >2; p=0.05) and a decreasing trend in the rates of cardiac perforation and device dislodgement. 8 Thirty-two device- or procedure-related major complications (defined as events resulting in death, permanent loss of device function as a result of mechanical or electrical dysfunction, hospitalisation, prolongation of hospitalisation by at least 48 hours, or system revision) were reported in 4% (29/726) of patients in the case series of 725 patients with TPS. All resulted in hospitalisation. 4 The risk of major complications for patients with TPS was 48% lower than for historical control group patients with transvenous systems through 12 months post-implant (hazard ratio 0.52; 95% CI 0.35 to 0.77; p=0.001). A risk reduction of 47% reduction was seen for hospitalisations and 82% risk reduction in system revisions. Across different subgroups of age, sex and comorbidities TPS reduced the risk of major complications compared with transvenous systems. 4 Thirteen device-related major complications (defined as events resulting in death, permanent loss of device function as a result of mechanical or electrical Page 6 of 62

7 dysfunction, hospitalisation, prolongation of hospitalisation by at least 48 hours, or system revision) were reported in 1.5% (12/795) of patients in the case series (registry) of 795 patients with TPS. All resulted in hospitalisation. 6 When compared these early safety results with another TPS investigational study (n=726) 4 the rates of major complications were lower (odds ratio 0.58, 95% CI 0.27 to 1.25, p=0.0691). 6 Major adverse events (loss of pacing and sensing) were reported in 2% (1/60) of patients in the LCP group and 3% (2/67) of patients (lead dislodgements) in the CTP group in the retrospective comparative case series of 127 patients (p=1.00). There was no difference in the rate of minor adverse events (10% [6/60] in the LCP group compared with 4.3% [3/67] in the CTP group, p=0.30). 10 Perforation and cardiac tamponade Right ventricular perforation leading to cardiac tamponade with haemodynamic collapse occurred during successful LCP implantation and repositioning in 1 patient in the case series of 33 patients. The patient had a massive ischaemic stroke 5 days later and eventually died after 2 weeks. 1 Cardiac perforations were reported in 1.6% (8/526) of patients (cardiac tamponade with intervention in 5 patients, cardiac perforation with intervention in 1 patient and pericardial effusion with no intervention in 8 patients) in the case series of 526 patients with LCP at a mean follow-up of 6.9 months. 2 Cardiac perforations or effusion occurred within 30 days in 1.6% (11/725) patients in the case series of 725 patients with TPS. Of these, 1 event occurred between 30 days to 6 months. All patients needed hospitalisation. 4 Cardiac perforation or effusion within 30 days was reported in 1 patient in the case series of 795 patients with TPS. Patient needed pericardiocentesis on the day of implantation and this was resolved. 6 Non-serious cardiac perfusion or perforations were reported in 4 other patients in the same study within 30 days. Two patients needed drainage or pericardial puncture or both and 2 other patients needed no intervention. 6 Vascular complications Vascular complications were reported in 1.2% (6/526) of patients (bleeding in 2 patients, arteriovenous fistula in 1 patient, pseudoaneurysm in 2 patients and failure of vascular closure device needing intervention in 1 patient) in the case series of 526 patients with LCP at a mean follow-up of 6.9 months. 2 Vascular complications at groin puncture site occurred within 30 days in fewer than 1% (5/725) of patients (atrioventricular fistula in 4 patients and Page 7 of 62

8 pseudoaneurysm 1 patient) in the case series of 725 patients. All patients needed hospitalisation. 4 Vascular complications within 30 days were reported in less than 1% (6/795) of patients (arteriovenous fistula in 1, hematoma in 2, incision site haemorrhage in 1, persistent lymphatic fistula in 1 and vascular pseudoaneurysm in 1) in the case series of 795 patients with TPS. 6 Venous thromboembolism Deep vein thrombosis (in 1) and pulmonary thromboembolism (in 1) occurred within 30 days in less than 1% (2/725) of patients in the case series of 725 patients with TPS. Both patients needed hospitalisation. 4 Deep vein thrombosis within 30 days was reported in 1 patient in the case series of 795 patients with TPS. 6 Device dislodgement and migration Device dislodgement at a mean 8 days (range 1 to 14 days) was reported in 1% (6/526) of patients in the case series of 526 patients with LCP at a mean followup of 6.9 months. Four leadless pacemakers dislodged to the pulmonary artery and 2 dislodged to the right femoral vein within 2 weeks after implantation. All devices were retrieved percutaneously and new LCPs were implanted. 2 Device dislodgement (as a result of tines not embedded properly) was reported in 1 patient 2 days post-implant in the case series of 795 patients with TPS. The device was successfully repositioned at 50 days post-implant, with normal pacing thresholds. 6 Device migration during implantation owing to inadequate fixation was reported in less than 1% (2/526) of patients in the case series of 526 patients with LCP at a mean follow-up of 6.9 months. 2 Elevated pacing threshold needing device retrieval and replacement Elevated pacing threshold needing percutaneous retrieval and new device replacement at a median 100 days (range 1 to 413 days) was reported in less than 1% (4/526) of patients in the case series of 526 patients with LCP at a mean follow-up of 6.9 months. 2 Elevated pacing thresholds were reported in less than 1% (2/725) of patients within 30 days in the case series of 725 patients with TPS. Both patients were hospitalised and loss of device function was noted in 1 patient. System revisions were done in both. 4 Page 8 of 62

9 Elevated pacing threshold was reported in 1 patient (within 30 days) in the case series of 795 patients with TPS. 6 Battery failures Battery failures (occurring at 2.9±0.4 years) with no instances of associated patient injury were reported in 2.3% (34/1423) of patients in a case series of 1,423 patients implanted with LCPs. 28 of these were asymptomatic and 6 were related to bradycardia. The mean time from last follow-up to detection of battery failure was 140±70 days (range 31 to 353 days). Limited analysis of these batteries revealed an increase in battery resistance caused by insufficient electrolyte availability at the cathode or anode interface and lack of adequate current needed for device. 8 of these devices were retrieved and re-implanted with another new LCP (n=6) or transvenous pacemakers (n=2). Eighteen devices were abandoned and revision was done with new LCPs (n=7) or new transvenous pacemakers (n=16) and close monitoring without revision was done in 8 patients. 3 Device retrieval and revisions Device retrievals were reported in 9% (3/33) of patients in the case series of 33 patients implanted with LCPs. In 1 patient the device was inadvertently implanted in the apex of heart with acceptable pacing performance but it was retrieved and a new LCP implanted in the right ventricle. In another patient, the device was retrieved and a single-chamber transvenous implantable cardioverter defibrillator was implanted but the patient developed ventricular tachycardia after 5 days and was readmitted 2 weeks later for implantable cardioverter defibrillator (ICD) shocks. In another patient, a malfunctioning device (caused by a battery problem, leading to an abrupt loss of communication) was retrieved and replaced with a new LCP. 1 Device retrievals and revisions were reported in 13% (181/1,423) of patients at a mean 1.7 years (range 0.2 to 4 years) in a case series of 1,423 patients implanted with LCPs. Indications for retrieval attempts included elevated pacing thresholds (n=8), need for device upgrade to defibrillator or biventricular pacemaker (n=9), elective explant (n=2), battery failure (n=8) and prophylactic explant based on battery failure advisory by the company (n=46). 37% (66/181) of the retrievals were successful and either new LCPs (n=29) or transvenous pacemakers (n=36) were re-implanted or no device was inserted (n=1). A total of 63% (115/181) of retrievals were unsuccessful (n=7) or abandoned with no retrieval (n=108). In 7 unsuccessful attempts (the LCP proximal button was inaccessible in 5 patients, docking button was in subvalvular apparatus and could not be snared in 1 and locking button detached from LCP during retrieval in1) new LCPs were implanted in 3 patients and transvenous pacemakers in 4 patients. In 108 abandoned patients, new LCPs were implanted in 5 and Page 9 of 62

10 transvenous pacemakers in 103. No adverse device-to-device interactions were identified. 3 System revisions were performed in less than 1% (5/725) of patients in the case series of 725 patients with TPS at 12-month follow-up. In 3 patients percutaneous retrieval attempt was done (1 was successfully retrieved and a new TPS implanted 16 days post-implant; 1 was unsuccessful because of inability to extract device at 259 days post-implant, and 1 was aborted because of fluoroscopy failure 229 days post-implant). In 2 other patients with loss of device function (because of pacemaker syndrome and elevated pacing threshold) the device was turned off without a retrieval attempt and concomitant transvenous pacemaker was implanted 32 and 44 days post-implant. 4 In a retrospective matched case control study comparing TPS (n=989) with transvenous pacemakers (historical control n=2,667), the risk of system revision through 24 months post-implant was 1.4% for patients with TPS (11 revisions in 10 patients), 75% lower than the 5.3% rate (95% confidence interval [CI] 4.4% 6.4%) for patients with transvenous pacemakers (123 revisions in 117 patients; hazard ratio 0.25; 95% CI ; p<0.001) with 107 (87%) occurring within 12 months. TPS revisions occurred between 5 to 430 days post-implant for elevated pacing thresholds (n=3), pacemaker syndrome (n=2), need for alternative therapy (n=2), cardiac failure (n=1), battery depletion (=1) and prosthetic valve endocarditis (n=1). Devices were disabled and left in situ in 7 patients, 3 were retrieved percutaneously (between 9 to 406 days post-implant) and 1 was surgically removed. 7 Cardiopulmonary arrest during implantation Cardiopulmonary arrest during implantation was reported in 1 patient in the case series of 526 patients with LCPs. 2 Arrhythmia during implantation Arrhythmia during implantation was reported in less than 1% (3/526) of patients (asystole in 1 and ventricular tachycardia or ventricular fibrillation in 2) in the case series of 526 patients with LCPs. 2 Other procedure-related serious adverse events Other procedure-related adverse events reported in 1 patient each in the case series of 526 patients with LCPS included haemothorax, angina pectoris, acute confusion and expressive aphasia, dysarthria and lethargy, contrast induced nephropathy, orthostatic hypotension with weakness, left leg weakness during implantation, pulmonary embolism, and ischaemic stroke. 2 Page 10 of 62

11 Other serious adverse events reported in the case series of 725 patients with TPS included cardiac failure in (n=6), acute myocardial infarction in (n=1), metabolic acidosis (n=1), pacemaker syndrome (n=2) and syncope or presyncope (n=2). 4 Other serious adverse events reported in the case series of 795 patients with TPS included pulmonary oedema (n=1), chest pain (n=1) and sepsis within 48 hours which was successfully treated using intravenous antibiotics (n=1). 6 Death Deaths were reported in 5.3% (28/526) of patients in the case series of 526 patients with LCPs. Of these, 68% (19/526) occurred within 6 months and 29% (8/526) between 6 and 12 months and 4% (1/526) after 12 months. None of these were device related, but less than 1% (2/526) were reported as procedure related. The cause of these deaths was classified as cardiac related in 4 patients, non-cardiac in 14 patients and unknown in 10 patients. 2 Deaths were reported in 11% (78/725) the case series of 725 patients with TPS at a mean follow-up of 16.4 months. These were because of sudden cardiac death (n=10), non-sudden cardiac death (n=22), non-cardiac death (n=43) and unknown reasons (n=2). 1 death was reported as procedure related (because of metabolic acidosis in a patient with end stage renal failure who had concomitant atrioventricular nodal ablation during pacemaker implantation). 4a, 4b Deaths were reported in 3% (22/795) of patients within 30 days in the case series of 795 patients with TPS. 1 death was reported as procedure related (because of pulmonary oedema and cardiac arrest). 6 Non-device or procedure-related serious adverse events Thirty-six non-device-related serious adverse events were reported in 5.5% (29/526) of patients at a mean follow-up of 6.9 months in the case series of 526 patients with LCPs. Of these 22 events were reported within 6 months in 6.3% (19/300) of patients in the primary cohort. 2 Anecdotal and theoretical adverse events In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never happened). For this procedure, specialist advisers listed the following anecdotal adverse event: infection. They considered that the Page 11 of 62

12 following were theoretical adverse events: device-device interaction and inability to communicate with programmer. The evidence assessed Rapid review of literature The medical literature was searched to identify studies and reviews relevant to leadless cardiac pacemaker implantation for bradyarrhythmias. The following databases were searched, covering the period from their start to : MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see the literature search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with bradyarrhythmias Leadless cardiac pacemaker implantation Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. Page 12 of 62

13 List of studies included in the IP overview This IP overview is based on about 6,000 patients who had leadless cardiac pacemaker implantation from 7 case series 1-4,6,8,10, 3 retrospective matched comparative studies 5,7,11 and 1 registry 9. Data were extracted from 5 studies for 2 of the case series, which were reported in separate phases. There is an overlap of patients in the included studies. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) are listed in the appendix. Table 2 Summary of key efficacy and safety findings on leadless cardiac pacemaker implantation for bradyarrhythmias Study 1 Reddy VY [2014] 1a, Knops RE (2015) 1b, Tjong FVY (2018) 1c Details Study type Case series (LEADLESS trial NCT ) Country The Netherlands, Germany, Prague (3 centres) Recruitment period December 2012-April 2013 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=33 patients with clinical indication for single-chamber pacing (VVIR) Mean age 77±8 years and 67% (22/33) male Patients older than 18 years, with a clinical indication for single-chamber (right ventricular) pacing (VVIR): permanent atrial fibrillation with atrioventricular block (67% [22/33]), normal sinus rhythm with 2 nd or 3 rd degree AV block with a low level of physical activity or short expected life span (18%, 6/33) or sinus bradycardia with infrequent pauses or unexplained syncope with electrophysiology findings (prolonged HV interval) (15%, 5/33) were included. Patients were excluded if pacemaker dependent, had a mechanical tricuspid valve prosthesis, pulmonary hypertension, pre-existing pacemaker or defibrillation leads or an inferior vena cava filter. Implantation of a self-contained leadless cardiac pacemaker (Nanostim Inc). Programming of the device was left to the discretion of the implanting physician. Pacing mode programmed to VVIR. Follow-up was done at pre-discharge, 2, 6 and 12 weeks post implantation. 90 days (n=33) 1a, mean 1.2 years (n=31) 1b, median 38 months (range 21 to 41 months) 1c Study funded by Nanostim Inc. 2 authors have received grant support from Nanostim, 1 received stock options, and 2 authors are employees of the company. Analysis Follow-up issues: Patients were retrospectively analysed in the intermediate follow-up (1 year) study. In the retrospective analysis, 2 patients from the initial study cohort were excluded. No patients were lost at final follow-up. Study design issues: small prospective multicentre study, primary safety endpoint was complication free rate (defined as serious adverse device effects) at 90 days and 40 months follow-up. Secondary endpoints included implant success (percentage of patients with an implanted and functioning LCP device), time, and measures of device performance. Page 13 of 62

14 Additionally LCP performance was assessed during magnet testing and 6 minute walk tests. An independent data and safety monitoring board reviewed the data. Data from medical records of 31 patients were retrospectively analysed in the intermediate follow-up (1 year) study (Knops 2015). Key efficacy and safety findings Efficacy Number of patients analysed: 33 Implantation outcomes Implant success rate 97% (32/33) Repositioning needed because of inadequate electrical measurements More than 1 LCP during the procedure (range 1-3) 29% (9/33) 15% (5/33)* Implantation duration, minutes 28±17 (range 11-74) Average time to hospital discharge, hours 31±20 (range ) *1 because of inadvertent placement of device in the left ventricle, 1 malfunction of the release knob, 1 delivery catheter damage related to tortuosity of the venous vasculature, 1 damage to the LCP helix during insertion and 1 difficulty with the wire deflection mechanism of the delivery catheter. Pacing performance Mean pacing threshold (at a 0.4- ms pulse width) Mean R- wave amplitude Mean impedance 12 weeks n=32 6 months n=32 12 months n=31 36 months 0.46± ±0.26V 0.43±0.30v 0.47± ± ±2.6mV 10.3±2.2 mv 627± ±205 ohms 627±209 ohms 10.8±2.3 mv 614±199 ohms Rate response sensor was activated in 61% (19/31) of patients at 12 months follow-up, and an adequate rate response was seen in all patients. Survival At 3 year follow-up, 74% (23/31) patients were alive. Safety Complications At 90 days follow-up % (n=33) Complication free rate 94 (31/33) Right ventricular perforation leading to cardiac tamponade with haemodynamic collapse during LCP implantation and repositioning (operated successfully but had a massive ischemic stroke 5 days later and eventually died after 2 weeks). Device-related complications 0 Device retrievals 2 LCP inadvertently implanted in the apex of heart with acceptable pacing performance (device was retrieved and new LCP implanted in the right ventricle) LCP was retrieved and a single chamber transvenous ICD implanted after 5 days (because of VT but readmitted 2 weeks later for ICD shocks because of VT) Rehospitalisation (1 for an elevated INR, 1 for an acute exacerbation of COPD, and 1 for VT) (3/33) At 1 year follow-up n=31 Device-related events 0 Rehospitalisation (not related to procedure or pacemaker function) 19 (6/31) At 3-year follow-up n=33 Freedom from SADEs 89.9 % (30/33) Device malfunction presenting an abrupt loss of communication and pacing attributable to battery malfunction at 37 months (LCP retrieved and replaced with a new LCP). Abbreviations used: COPD, chronic obstructive pulmonary disease; INR, international normalised ratio; LCP, leadless cardiac pacemaker; ICD, implantable cardioverter defibrillator; VT, ventricular tachycardia. 1 Page 14 of 62

15 Study 2 Reddy VY (2015) 2 Details Study type Case series (LEADLESS II pacemaker IDE study NCT ) Country US, Canada and Australia (56 centres) Recruitment period February 2014 to June 2015 Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding n=526 patients who needed permanent single-chamber ventricular pacing Mean 75±8 years; 62% (325/526) male patients with indications for permanent single-chamber ventricular pacing, including chronic atrial fibrillation with atrioventricular or bifascicular bundle-branch block (n=294), sinus rhythm with seconddegree or third-degree atrioventricular block (n=46) and a low level of physical activity or a shortened expected life span, or sinus bradycardia with infrequent pauses or unexplained syncope with an abnormal electrophysiological study (n=186). Patients were excluded if they had a mechanical tricuspid-valve prosthesis, pulmonary arterial hypertension, pre-existing endocardial pacing or defibrillation leads, or an inferior vena cava filter or if they had had cardiovascular or peripheral vascular surgery within 30 days before enrolment. Implantation of a self-contained leadless cardiac pacemaker (Nanostim LP). Programming of the device was left to the discretion of the implanting physician. Pacing mode programmed to VVIR. Follow-up assessments done at 2, 4, 12 weeks and 6 months and thereafter every 6 months. Primary cohort: minimum 6 months (n=300); total cohort: mean 6.9±4.2 months (n=526) This premarket study was funded by St. Jude Medical and approved by FDA. Analysis Study design issues: interim analysis of a large ongoing prospective multicentre study in 3 countries. Data collection and analysis was done by sponsor. The primary efficacy end point was both an acceptable pacing threshold ( 2.0 V at 0.4 ms) and an acceptable sensing amplitude (R wave 5.0 mv, or a value equal to or greater than the value at implantation) at 6 months. The primary safety end point was freedom from device-related serious adverse events at 6 months. Analysis was performed on data from the first 300 patients who completed 6 months of follow-up and additional outcomes (operator experience, device-related and non-device-related adverse events) were reported for all patients who were enrolled. The rates of the efficacy end point and safety end point were compared with performance goals (based on historical data from recipients of conventional transvenous pacemakers) of 85% and 86%, respectively. The study used the standard definition of serious adverse events. Study population issues: varied group of patients. Page 15 of 62

16 Key efficacy and safety findings Efficacy Number of patients analysed: 526 Implantation outcomes Implant success rate 95.8% (504/526) No device repositioning needed Repositioning needed because of inadequate electrical measurements (range 1-3) Implantation duration, minutes Average time to hospital discharge, days 70.2% (354/504) 29.8% (150/504) 28.6±17.8 (range 11-74) 1.1±1.7 (range 0-33) Pacing performance in 90% [270/300] of primary cohort (95% CI, 86.0 to 93.2, p = 0.007) Mean pacing threshold (at a 0.4- ms pulse width) Mean R- wave amplitude Mean impedanc e Baseline 12 months P valu e 0.82±0.6 9 V 7.8±2.9 mv 700±295 ohms 0.58±0.31 V 9.2±2.9 mv 456±111 ohms <0.01 <0.01 <0.01 Safety Complications Complication free rate Device-related serious adverse events Primary cohort % (n=300) 93.3 (280/300) 95% CI, 89.9 to 95.9; p< (20/300) 22 events Cardiac perforation 1.3 (4/300) Arrhythmia during implantation Cardiopulmonary arrest during implantation Vascular complications Device dislodgement with retrieval (at 8 days, range 1-14) Device migration during implantation Elevated pacing thresholds needing device retrieval and replacement (median 100, range days) Non-device-related serious adverse events (2 with worsening heart failure needed device retrieval and cardiac resynchronisation therapy) (tamponade 1, perforation1-with interventions; 2 pericardial effusions with no intervention) 0.6 (2/300) (asystole 1,VT or VF 1) Total cohort % (n=526) 6.5 (34/526) 40 events 1.6 (8/526) (tamponade 5, perforation 1-with interventions; pericardial effusion with no intervention 2) 0.6 (3/526) (1/526) 1.3 (4/300) Bleeding 2, arteriovenous fistula 1, pseudoaneurysm 1) (asystole 1, VT or VF 1) 1.2 (6/526) 1.7 (5/300) 1.1 (6/526) (2/526) 1.3 (4/300) 0.8 (4/526) 6.3% (19/300) 22 events (Bleeding 2,arteriovenous fistula 1, pseudoaneurysm 2, failure of vascular closure device needing intervention 1) (4 LCPs dislodged to the pulmonary artery and 2 dislodged to the right femoral vein within 2 weeks after implantation, all were removed and new LCPs implanted) 5.5 (29/526) 36 events Deaths* 5.3 (28/526) Page 16 of 62

17 Other device-related serious adverse events reported in 1 patient each included haemothorax, angina pectoris, acute confusion and expressive aphasia, dysarthria and lethargy, contrast induced nephropathy, orthostatic hypotension with weakness, left leg weakness during implantation, pulmonary embolism, and ischaemic stroke. *68% (19/526) occurred in 6 months and 29% (8/526) between 6 and 12 months and 4% (1/526) after 12 months. None were device related, but 0.4% (2/526) were procedure related. Only 4 deaths were cardiac related. Influence of operator-experience- on device-related adverse events The rate of device-related serious adverse events was 6.8% for the initial 10 cases versus 3.6% for the subsequent implants (p = 0.56). Abbreviations used: CI, confidence interval; LCP, leadless cardiac pacemaker; VT, ventricular tachycardia; VF, ventricular fibrillation. Page 17 of 62

18 Study 3 Lakkireddy D (2017) 3 Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case series Worldwide (32 centres in Europe, US, Canada, and Australia) (data from 3 trials NCT , NCT , NCT ) n=1423 patients who had a leadless pacemaker (Nanostim) Not reported Data from patients who had a right ventricular active fixation leadless pacemaker within 3 multicentre clinical trials (NCT , NCT , NCT ). Inclusion criteria as described in studies above. Leadless cardiac pacemaker (Nanostim) implanted (technique is described in procedure description above) Follow-up until March 2017 (4 years 3 months) Study was funded by St. Jude Medical and approved by FDA; 2 authors were consultants to the manufacturer and received honorarium. Clinical trials included in this study were funded by St. Jude Medical. Analysis Study design issues: large retrospective study; data on incidence of battery failures and acute and chronic retrieval of leadless pacemakers were collected and assessed from 3 multicentre clinical studies worldwide. Patient management in clinical trials was based on the recommendations included in the battery advisory issued by the company (in October 2016) after 7 cases of battery malfunction leading to loss of pacing and communication were reported. Enrolment in these studies was suspended. In retrieval attempts, adverse events related to the procedure and reason for retrieval were also collected. 3 retrievals conducted outside studies are also included here. Page 18 of 62

19 Key efficacy and safety findings Safety Number of patients analysed: 1423 LCP battery failures Battery failures (occurring at 2.9±0.4 years [range years] with no instances of associated patient harm or injury) % (n) Asymptomatic n=28 Symptomatic related to bradycardia n=6 2.3 (34/1423) (30 in Europe, 3 in US, and 1 in Australia). IP 1192 [IPG626] LCP retrieved n=8 (re-implanted another new LCP in 6, TV pacemaker in 2) LCP abandoned and revised No revision and close monitoring n=8 n=18 (re-implanted new LCP in 7 and new TV pacemaker in16) The mean time from last follow-up to detection of battery failure is 140±70 days (range days). Limited analysis did not reveal clear predictors of failure. Failures were attributed to reduced electrolyte in the battery leading to an increased battery resistance, and lack of adequate current needed for device. LCP retrievals and revisions % (n) All LCP revisions 12.7 (181/1423) Retrieval attempts LCP retrieval successful (implant duration mean 1.7 years; range years) LCP retrieval unsuccessful or abandoned N=73 (20 before advisory and 53 after advisory) (Indications for retrieval: elevated pacing thresholds (n=8), need for device upgrade to defibrillator or biventricular pacemaker (n=9), elective explant (n=2), battery failure (n=8) and prophylactic explant based on advisory (n=46)). 37 (66/181) before advisory in 19 and after advisory in 47 (re-implanted with another LCP in 29, with TV pacemaker in 36, no device placed in 1) 63 (115/181) 1. **unsuccessful retrieval attempts in 7 re-implanted with another LCP in 4 and TV pacemaker in 3 2. LCPs abandoned with no retrieval attempt in 108- re-implanted with new LCP in 5 and TV pacemaker in 103 (no adverse device-to-device interactions identified) **the LCP proximal button was inaccessible in 5 patients because of proximal button could not be accessed, docking button was in subvalvular apparatus and could not be snared, locking button detached from LCP during retrieval. There was no statistically significant difference in retrieval success rates over time (0-1 year 86% [n=22], 1-2 years 93% [n=30], more than 2 years 90% [n=21]), p>0.05). LCP retrieval-related adverse events SADEs Arteriovenous fistula (related to prophylactic replacement of device based on the advisory) 1 Docking button detached and LCP migrated to the pulmonary artery during retrieval attempt, button was not retrieved (related to prophylactic replacement of device based on the advisory) Non-SADEs Tricuspid valve damage with trivial or moderate regurgitation(no long term sequelae) 2 Atrial flutter (had an ablation procedure) 1 N 1 Deaths =41 4 occurred after 2.6 years from implantation and 37 occurred at 0.7 years after implantation. No signs of battery problems were seen at visit before death (mean 64.4±53.8 days). 4 devices analysed by the manufacturer were found to be working properly. Abbreviations used: LCP, leadless cardiac pacemaker; SADE, serious adverse device effects; TV, transvenous. Page 19 of 62

20 Study 4 Reynolds D (2016) 4a ; Duray GZ (2017) 4b Details Study type Prospective case series (FDA IDE Micra TPS trial NCT ) Country Recruitment period Study population and number Age and sex Patient selection criteria Worldwide (56 centres in 19 countries: US, Europe, Asia, Australia and Africa) n=725 patients with class I or II guideline indications for right ventricular pacing posthoc analysis 725 transcatheter pacing system (TPS) versus 2667 transvenous pacemakers in the historical control cohort Mean 75.9 years; 58.8% (426/725) male Patients who met class I or II guideline-based indications for de novo right ventricular pacing (i.e., for bradycardia because of atrial tachyarrhythmia (64%), sinus node dysfunction (17.5%), atrioventricular node dysfunction (14.8%), or other causes (3.7%)) were considered to be suitable candidates for singlechamber ventricular demand (VVI) pacing, were not prevented from participating as a result of coexisting conditions were included. Patients with an existing pacemaker or implantable cardioverter defibrillator were not included in the study. Technique The Micra transcatheter pacemaker, a single chamber ventricular pacemaker was implanted by 94 physicians. Implant technique is described in procedure description. Follow-up assessments were done at 1, 3 and 6 months and thereafter biannually for at least 12 months. Follow-up 6 months (Reynolds D 2016); mean 16.4 ± 4.9 months (Duray GZ 2017) Conflict of interest/source of funding Study funded by Medtronic; sponsor assisted in data analyses and publication. Most authors received consulting fees or grants from Medtronic. Analysis Follow-up issues: large study with longer follow-up. No patients were followed beyond 2 years. Study design issues: large multicentre prospective study, Reynold D 2016 is a planned early performance interim analysis. The primary safety end point was freedom from system-related or procedure-related major complications. The primary efficacy end point was the percentage of patients with low and stable pacing capture thresholds at 6 months ( 2.0 V at a pulse width of 0.24 ms and an increase of 1.5 V from the time of implantation). Duray 2017 assessed long-term safety (at 12 months) and electrical performance (at 24 months). The safety and efficacy end points were evaluated against performance goals (based on historical data from recipients of conventional transvenous pacemakers for which individual patient level data was available) of 83% and 80%, respectively. The analysis of the primary end points began when 300 patients reached 6 months of follow-up. A post hoc analysis comparing the rates of major complications with those in a predefined historical control group of 2,667 patients with transvenous pacemakers from 6 previously published studies was also performed. Safety events were reviewed by an independent clinical events committee. Study population issues: There were statistically significant differences between the study patients and the control patients with regard to baseline characteristics. Study patients were older and had more comorbidities. One additional successful implant occurred after the early performance analysis. 36% of patients were without persistent atrial arrhythmia at baseline. Other issues: study used a self-defined safety end point. Page 20 of 62

21 Key efficacy and safety findings Efficacy Number of patients analysed: 725 study group versus 2667 historical control group Implantation outcomes Implant success rate 99.2% (719/725) Unsuccessful implantations* 0.8% (6/725) Implantation duration 23.0±15.3 minutes (range minutes) *3 with cardiac perforations, 1 with pericardial effusion, 1 with tortuous venous anatomy, and 1 in whom pacing threshold could not be achieved. Evaluation of efficacy against the performance goal of 80% (based on historical data) The rate of the primary efficacy end point was 98.3% (95% CI, 96.1 to 99.5; P<0.001) among 292 of 297 patients with paired 6-month data. Mean pacing threshol d (at a 0.24-ms pulse width) Mean R-wave amplitu de Mean pacing impeda nce At implan tation (n=725 ) 6 mont hs (n=30 0) 0.63 V 0.54 V 11.2 mv 724 ohms 15.3 mv 627 ohms 12 month s (n=630 ) 0.60 ± 0.38 V 15.1 mv 596 ohms 24 month s (n=58) 0.53 ± 0.23 V 15.5 mv 596 ohms The projected battery longevity was 12.1 years. Safety Evaluation of safety against the performance goal of 83% (based on historical data) The Kaplan Meier estimate of the rate of the primary safety end point at 6 months was 96.0% (95% CI, 93.9 to 97.3; P<0.001). The long-term safety objective was achieved with a freedom from major complication rate of 96.0% at 12 months (95% confidence interval 94.2% 97.2%; P <0.0001). Complications Procedure-related death (because of metabolic acidosis in patient with end stage renal failure who had concomitant atrioventricular nodal ablation during TPS implantation) Within 30 days (n=725) 6 months % (n=725) >6 months % (n=726) Device-related deaths 0 Systemic-related deaths 77 Device- and procedurerelated major complications* (all resulted in hospitalisation) Cardiac perforations or effusion Vascular complications (atrioventricular fistula 4 or pseudoaneurysm 1) Venous thromboembolism (DVT, pulmonary embolism) Elevated pacing threshold 2.89 (21/725) 24 events 0.8 (6/725) 6 events 0.2 (2/726) 2 events Total % (n=726) 3.99% (29/726) 32 events (11/725) (5/726) (2/726) (2/726) Other events (12/726) Acute myocardial infarction (1/726) Cardiac failure (6/726) Metabolic acidosis (1/726) Pacemaker syndrome (2/726) Syncope or presyncope (2/726) Device dislodgements Device- or procedurerelated infections Systemic infections 26 0 Page 21 of 62

22 Revisions 5 Device was turned off without retrieval and TV pacemaker implanted in patients with loss of device function (because of pacemaker syndrome and elevated pacing threshold) Device retrievals (in 1 with loss of capture, the device was retrieved and a new TPS implanted 16 days post-implant; 1 was unsuccessful because of inability to extract device at 259 days post-implant, 1 was aborted because of fluoroscopy failure 229 days post-implant) * Major complications were defined as events resulting in death, permanent loss of device function as a result of mechanical or electrical dysfunction, hospitalisation, prolongation of hospitalisation by at least 48 hours, or system revision. Major complications at 12 months between study and historical control patients Major complications Death Hospitalisations Prolonged hospitalisations System revisions Loss of device function Study group % (n=726) 4.0 (2.8 to 5.8%) 0.1 (0 to 1.0%) 2.3 (1.4 to 3.7%) 2.2 (1.4 to 3.6%) 0.7 (0.3 to 1.7%) 0.3 (0.1 to 1.1%) Historical control group % (n=2667) Relative risk reduction (95% CI) 7.6 (6.6 to 8.7%) 48% (23 to 65%) 0% NE hazard ratio 0.52; 95% CI ; p < (3.4 to 5.0%) 47 (11 to 69%) 2.4 (1.9 to 3.1%) 9 (-57 to 47%) 3.8 (3.1 to 4.6%) 82 (55 to 93%) 0 NE The rates of fixation-related events (device or lead dislodgements) were statistically significantly higher in the historical control cohort than in the study cohort. The rates of access-site events, pacing issues, and cardiac injury events did not differ statistically significantly between the cohorts. Across subgroups of age, sex, and comorbidities, TPS was associated with a reduced risk of major complications compared with TV systems. Abbreviations used: CI, confidence interval; DVT, deep vein thrombosis; NE, not estimable; TV, transvenous; TPS, transcatheter pacing system. Page 22 of 62